Study of Tacrolimus vs Mycophenolate Mofetil in Pediatric Patients With Nephrotic Syndrome

Nephrotic Syndrome in Children Clinical Trial

— STAMP  

Official title:

Study of Tacrolimus vs Mycophenolate Mofetil in Pediatric Patients With Frequently Relapsing or Steroid Dependent Nephrotic Syndrome: a Randomized, Multicenter, Open-label, Parallel-arm Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04048161
• Other study ID #: STAMP
• Status: Completed
• Phase: Phase 4
• Start date: November 12, 2019
• Est. completion date: July 12, 2023

Study information

• Verified date: October 2023
• Source: The Children's Hospital of Zhejiang University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary nephrotic syndrome accounts for approximately 90% of the total number of nephrotic syndrome in childhood and it is the most common glomerular disease in children. Although treatment with steroids is uesful for primary nephrotic syndrome, proning to cause frequent relapse/steroid-dependent nephrotic syndrome after treatment, and the usage of immunosuppressive agents has become a new choice for the treatment of such patients. This study is a prospective, randomized, multicenter, open, parallel controlled trial, evaluating the efficacy and safety of steroid combined with the immunosuppressive agents which are tacrolimus and mycophenolate mofetil to children who with frequently relapsing or steroid-dependent nephrotic syndrome, all we wish to obtain the proper drug choice and individualized treatment options for children with nephrotic syndrome.

Description:

Although steroids are recognized as first-line treatments for nephrotic syndrome, the vast majority of children relapse, and about half of them have frequent relapse or steroids dependence after treatment with steroids alone. Some children experienced steroids-resistance after multiple relapses, and eventually developed into chronic kidney dysfunction. Long-term or repeated application of large doses of steroids will lead to side effects such as obesity, growth retardation, and hypertension. Although the treatment of steroids with immunosuppressive agents is a new choice for the treatment of such patients, traditional immunosuppressive agents such as cyclophosphamide and cyclosporine A will bring some serious irreversible side effects, while immunosuppressive agents tacrolimus has the dual effects of immunosuppression and podocyte protection, and is more widely used in the department of nephrology, what's more, the other immunosuppressive agents mycophenolate mofetil has advantage of no kidney toxic, less adverse reactions and higher safety, which gradually being valued by nephrologists in recent years. This study mainly compares the efficacy and safety of tacrolimus and mycophenolate mofetil in the treatment of children with frequently relapsing or steroids-dependent nephrotic syndrome, in order to provide a more effective and safer treatment for children with nephrotic syndrome as well as the therapeutic medication options.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 270
• Est. completion date: July 12, 2023
• Est. primary completion date: May 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

Inclusion Criteria:

• Sensitive but frequent relapses or steroids dependence nephrotic syndrome
• Age: 2 to 18 years old
• Normal renal function: estimated glomerular filtration rate =90ml/min/1.73m2
• Morning urine protein <1+ or urine protein-creatinine ratio <0.2g/g (<20 mg/mmol) for 3 consecutive days and above when in enroll
• No tacrolimus, mycophenolate mofetil, cyclosporine A, rituximab or cyclophosphamide was used within 2 years prior to the enrollment

Exclusion Criteria:

• steroids-resistant nephrotic syndrome
• Family history of nephrotic syndrome, chronic glomerulonephritis or uremia
• Leukopenia (White Blood Cells = 3.0 * 10^9 / L)
• Moderate to severe anemia (hemoglobin <9.0 g/dL)
• Thrombocytopenia (platelet count <100*10^12/L)
• Positive Hepatitis B virus serological indicators (Hepatitis B surface antigen or / and Hepatitis B virus e antigen or / and Hepatitis B core antibody), Hepatitis C virus-positive or patients with abnormal liver function (2 or more times of alamine aminotransferase or total bilirubin was exceeded the normal value, and continued to rise for 2 weeks)
• There are chronic active infections such as Epstein-Barrvirus, cytomegalovirus or Mycobacterium tuberculosis, and the usage of steroids and immunosuppressive agents may aggravate the state of an illness
• Secondary nephrotic syndrome (such as purpuric nephritis, lupus nephritis, etc.)
• Those who with hematological or endocrine system diseases as well as serious organs illness such as heart, liver or kidney
• Those who with other autoimmune diseases or primary immunodeficiencies or tumors
• Those who was known to be sensitized to tacrolimus, mycophenolate mofetil, glucocorticoids, or any of the above drugs
• Those who have participated in other clinical trials within three months prior to the enrollment
• Those who was not suitable for participating this study judged by investigator

Related Conditions & MeSH terms

• Nephrosis
• Nephrotic Syndrome
• Nephrotic Syndrome in Children
• Syndrome

Intervention

Drug:
• Tacrolimus
The patients will be divided into two groups randomly. Tacrolimus dose: 0.05-0.10 mg/kg/day, BID. The concentration for tacrolimus is 5-10 ng/ml,then reduce the dosage of drugs to maintian the concentration for tacrolimus is < 5ng/ml. Total duration : 1 year. Steroid dose: 1.0-1.5 mg/kg, qod or 0.5-0.75 mg/kg/day, qd, then gradually taper the steroid to 5mg/day.
• Mycophenolate Mofetil
The patients will be divided into two groups randomly. Mycophenolate Mofetil dose: 20~30mg/kg/day,BID. The concentration for MPA-AUC is 30~50 µg.h/ml,then reduce the dosage of drugs to maintian the concentration for MPA-AUC is =40 µg.h/ml. Total duration : 1 year. Steroid dose: 1.0-1.5 mg/kg, qod or 0.5-0.75 mg/kg/day, qd, then gradually taper the steroid to 5mg/day.

Locations

Country	Name	City	State
China	Peking University First Hospital	Beijing	Beijing
China	Second Xiangya Hospital of Central South University	Changsha	Hunan
China	Chengdu Women and Children's Center Hospital	Chengdu	Shichuan
China	Children's Hospital of Chongqing Medical University	Chongqing	Chongqing
China	First Affiliated Hospital of Zhongshan Medical University	Guangzhou	Guangdong
China	The Children Hospital of Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Shandong Provincial Hospital	Jinan	Shandong
China	Nanjing Children's Hospital	Nanjing	Jiangsu
China	Children's Hospital of Fudan University	Shanghai	Shanghai
China	Children's Hospital of Soochow University	Suzhou	Jiangsu
China	Tongji Hospital	Wuhan	Hubei
China	Henan Children's Hospital	Zhengzhou	Henan

Sponsors (12)

Lead Sponsor

Collaborator

The Children's Hospital of Zhejiang University School of Medicine

Chengdu Women and Children's Center Hospital, Children's Hospital of Chongqing Medical University, Children's Hospital of Fudan University, Children's Hospital of Soochow University, First Affiliated Hospital of Zhongshan Medical University, Henan Provincial People's Hospital, Nanjing Children's Hospital, Peking University First Hospital, Second Xiangya Hospital of Central South University, Shandong Provincial Hospital, Tongji Hospital

Country where clinical trial is conducted

China, 

References & Publications (12)

Briggs WA, Choi MJ, Scheel PJ Jr. Successful mycophenolate mofetil treatment of glomerular disease. Am J Kidney Dis. 1998 Feb;31(2):213-7. doi: 10.1053/ajkd.1998.v31.pm9469489. — View Citation

Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003 Aug 23;362(9384):629-39. doi: 10.1016/S0140-6736(03)14184-0. — View Citation

Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J. Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis. 2003 Dec;42(6):1107-13. doi: 10.1053/j.ajkd.2003.08.010. — View Citation

Gellermann J, Weber L, Pape L, Tonshoff B, Hoyer P, Querfeld U; Gesellschaft fur Padiatrische Nephrologie (GPN). Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome. J Am Soc Nephrol. 2013 Oct;24(10):1689-97 — View Citation

Koefoed-Nielsen PB, Karamperis N, Hojskov C, Poulsen JH, Jorgensen KA. The calcineurin activity profiles of cyclosporin and tacrolimus are different in stable renal transplant patients. Transpl Int. 2006 Oct;19(10):821-7. doi: 10.1111/j.1432-2277.2006.003 — View Citation

Neidle S, Goodwin GH. A homology-based molecular model of the proline-rich homeodomain protein Prh, from haematopoietic cells. FEBS Lett. 1994 May 30;345(2-3):93-8. doi: 10.1016/0014-5793(94)00446-3. — View Citation

Ren H, Shen P, Li X, Pan X, Zhang W, Chen N. Tacrolimus versus cyclophosphamide in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a randomized controlled trial. Am J Nephrol. 2013;37(1):84-90. doi: 10.1159/000346256. Epub 2013 — View Citation

Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987 Jun;34(3):571-90. doi: 10.1016/s0031-3955(16)36251-4. — View Citation

Sepe V, Libetta C, Giuliano MG, Adamo G, Dal Canton A. Mycophenolate mofetil in primary glomerulopathies. Kidney Int. 2008 Jan;73(2):154-62. doi: 10.1038/sj.ki.5002653. Epub 2007 Nov 7. — View Citation

Shaw KT, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A, Hogan PG. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11205-9. doi: 10 — View Citation

Tarshish P, Tobin JN, Bernstein J, Edelmann CM Jr. Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children. J Am Soc Nephrol. 1997 May;8(5):769-76. doi: 10.1681/ASN. — View Citation

Wong W. Idiopathic nephrotic syndrome in New Zealand children, demographic, clinical features, initial management and outcome after twelve-month follow-up: results of a three-year national surveillance study. J Paediatr Child Health. 2007 May;43(5):337-41 — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	1-year relapse-free survival rate	The rate of no relapse within 1 year	1-year period after randomization
Secondary	Relapse of nephrotic syndrome during 12 months after randomization	Proportion of patients with one or more relapse(s) of nephrotic syndrome	1-year period after randomization
Secondary	Number of relapses during 12 months follow up	Number of nephrotic syndrome relapses per patient year during the 12 months period after randomization	1-year period after randomization
Secondary	The first time to relapse	The first time to relapse after patients taking part in this study	1-year period after randomization
Secondary	Cumulative prednisone dosage (milligrams per kilogram per year)	The total dosage of prednisones from the beginning to the end of the trial	1-year period after randomization
Secondary	Change in serum cholesterol, hemoglobin and blood albumin of the patients	The changes of serum cholesterol, hemoglobin and blood albumin in each follow-up during the study	1-year period after randomization
Secondary	Change in renal function of the patients	The change for renal function was judged by the changes of serum creatinine and estimated glomerular filtration rate in each follow-up during the study	1-year period after randomization
Secondary	Change in anthropometry and growth velocity during 12-month period after randomization	Changes in standard deviation scores for weight, height and body mass index during 12-month period after randomization	1-year period after randomization
Secondary	Adverse event	The number of harmful reactions and the types of adverse events during the study	1-year period after randomization